Hormonal and metabolic signals interact with neural circuits orchestrating behavior to guide food intake. Neuroimaging techniques such as functional magnetic resonance imaging (fMRI) enable the identification of where in the brain particular mental processes like desire, satiety and pleasure occur. Once these neural circuits are described it then becomes possible to determine how metabolic and hormonal signals can alter brain response to influence psychological states and decision-making processes to guide intake. Here, we provide an overview of the contributions of functional neuroimaging to the understanding of how subjective and neural responses to food and food cues interact with metabolic/hormonal factors. [Hide abstract]

The gut microbiome has been proposed to play a causal role in obesity. Here, we review the historical context for this hypothesis, highlight recent key findings, and critically discuss issues central to further progress in the field, including the central epistemological problem for the field: how to define causality in the relationship between microbiota and obesity phenotypes. Definition of such will be critical for the field to move forward. [Hide abstract]

Genome-wide association studies have revealed that SNPs in the first intron of FTO (Fat mass and Obesity related) are robustly associated with body mass index and obesity. Subsequently, it has become clear that this association with body weight, and increasingly food intake, is replicable across multiple populations and different age groups. However, to date, no conclusive link has been made between the risk alleles and FTO expression or its physiological role. FTO deficiency leads to a complex phenotype including postnatal mortality and growth retardation, pointing to some fundamental developmental role. Yet, the weight of evidence from a number of animal models where FTO expression has been perturbed indicates some role for FTO in energy homoeostasis. In addition, emerging data points to a role for FTO in the sensing of nutrients. In this review, we explore the in vivo and in vitro evidence detailing FTO's different faces and discuss how these might link to the regulation of body weight. [Hide abstract]

ReviewEmerging role of glial cells in the control of body weightCristina García-Cáceres, Esther Fuente-Martín, Jesús Argente, Julie A. Chowen

Glia are the most abundant cell type in the brain and are indispensible for the normal execution of neuronal actions. They protect neurons from noxious insults and modulate synaptic transmission through affectation of synaptic inputs, release of glial transmitters and uptake of neurotransmitters from the synaptic cleft. They also transport nutrients and other circulating factors into the brain thus controlling the energy sources and signals reaching neurons. Moreover, glia express receptors for metabolic hormones, such as leptin and insulin, and can be activated in response to increased weight gain and dietary challenges. However, chronic glial activation can be detrimental to neurons, with hypothalamic astrocyte activation or gliosis suggested to be involved in the perpetuation of obesity and the onset of secondary complications. It is now accepted that glia may be a very important participant in metabolic control and a possible therapeutical target. Here we briefly review this rapidly advancing field. [Hide abstract]

Researchers analyse hormones to draw conclusions from changes in hormone concentrations observed under specific physiological conditions and to elucidate mechanisms underlying their biological variability. It is, however, frequently overlooked that also circumstances occurring after collection of biological samples can significantly affect the hormone concentrations measured, owing to analytical and pre-analytical variability. Whereas the awareness for such potential confounders is increasing in human laboratory medicine, there is sometimes limited consensus about the control of these factors in rodent studies. In this guide, we demonstrate how such factors can affect reliability and consequent interpretation of the data from immunoassay measurements of circulating metabolic hormones in rodent studies. We also compare the knowledge about such factors in rodent studies to recent recommendations established for biomarker studies in humans and give specific practical recommendations for the control of pre-analytical conditions in metabolic studies in rodents. [Hide abstract]

Leptin action in the brain signals the repletion of adipose energy stores, suppressing feeding and permitting energy expenditure on a variety of processes, including reproduction. Leptin binding to its receptor (LepR-b) promotes the tyrosine phosphorylation of three sites on LepR-b, each of which mediates distinct downstream signals. While the signals mediated by LepR-b Tyr1138 and Tyr985 control important aspects of energy homeostasis and LepR-b signal attenuation, respectively, the role of the remaining LepR-b phosphorylation site (Tyr1077) in leptin action has not been studied. To examine the function of Tyr1077, we generated a “knock-in” mouse model expressing LepR-b F1077, which is mutant for LepR-b Tyr1077. Mice expressing LepR-b F1077 demonstrate modestly increased body weight and adiposity. Furthermore, females display impairments in estrous cycling. Our results suggest that signaling by LepR-b Tyr1077 plays a modest role in the control of metabolism by leptin, and is an important link between body adiposity and the reproductive axis. [Hide abstract]

Decreased β-cell mass reflects a shift from quiescence/proliferation into apoptosis, it plays a crucial role in the pathophysiology of diabetes. A major attempt to restore β-cell mass and normoglycemia is to improve β-cell survival. Here we show that switching off the Fas pathway using Fas apoptotic inhibitory protein (Faim/TOSO), which regulates apoptosis upstream of caspase 8, blocked β-cell apoptosis and increased proliferation in human islets. TOSO was clearly expressed in pancreatic β-cells and down-regulated in T2DM. TOSO expression correlated with β-cell turnover; at conditions of improved survival, TOSO was induced. In contrast, TOSO downregulation induced β-cell apoptosis. Although TOSO overexpression resulted in a 3-fold induction of proliferation, proliferating β-cells showed a very limited capacity to undergo multiple rounds of replication. Our data suggest that TOSO is an important regulator of β-cell turnover and switches β-cell apoptosis into proliferation. [Hide abstract]

Ghrelin, a circulating gut-hormone, has emerged as an important regulator of growth hormone release and appetite. Ghrelin-immunopositive neurons have also been identified in the hypothalamus with a unique anatomical distribution. Here, we report that ghrelin-labeled neurons receive direct synaptic input from the suprachiasmatic nucleus, the central circadian timekeeper of the brain, and lateral geniculate nucleus, a visual center, and project synaptically to the lateral hypothalamic orexin/hypocretin system, a region of the brain critical for arousal. Hypothalamic ghrelin mRNA oscillates in a circadian pattern peaking in the dark phase prior to the switch from arousal to sleep. Ghrelin inhibits the electrophysiological activity of identified orexin/hypocretin neurons in hypothalamic slices. These observations indicate that the hypothalamic neurons identified by ghrelin immunolabeling may be a key mediator of circadian and visual cues for the hypothalamic arousal system. [Hide abstract]

Food intake is generally accepted to be regulated by the melanocortin system, however recent data suggests that mesolimbic dopaminergic neurons also influence food intake. Whether dopamine signaling is crucial for the acute effect of leptin on feeding is unknown. Using pharmacological and genetic strategies, we tested the hypothesis that the acute inhibitory effect of leptin on food intake is partially mediated by dopamine. Dopamine D2 but not D1 receptor blockade attenuated the acute hypophagic effect of leptin in fasted mice. Additionally, mice lacking the D2R (D2R KO) exhibited an attenuated response to leptin. Conversely, dopamine receptor blockade had no effect on the acute hypophagic effect of melanocortin stimulation or the hyperphagic effect of ghrelin. These findings suggest that dopaminergic pathways do not constitute a normal part of melanocortin-dependent feeding regulation and that the dopaminergic neurocircuitry typically associated with regulation of hedonic feeding likely contributes to feeding regulation by leptin. [Hide abstract]

Obesity, type 2 diabetes, and related diseases represent major health threats to modern society. Related pathophysiology of impaired neuronal function in hypothalamic control centers regulating metabolism and body weight has been dissected extensively and recent studies have started focusing on potential roles of astrocytes and microglia. The hypothalamic vascular system, however, which maintains the microenvironment necessary for appropriate neuronal function, has been largely understudied. We recently discovered that high fat/high sucrose diet exposure leads to increased hypothalamic presence of immunoglobulin G (IgG1). Investigating this phenomenon further, we have discovered a significant increase in blood vessel length and density in the arcuate nucleus (ARC) of the hypothalamus in mice fed a high fat/high sucrose diet, compared to matched controls fed standard chow diet. We also found a clearly increased presence of α-smooth muscle actin immunoreactive vessels, which are rarely present in the ARC and indicate an increase in the formation of new arterial vessels. Along the blood brain barrier, an increase of degenerated endothelial cells are observed. Moreover, such hypothalamic angiogenesis was not limited to rodent models. We also found an increase in the number of arterioles of the infundibular nucleus (the human equivalent of the mouse ARC) in patients with type 2 diabetes, suggesting angiogenesis occurs in the human hypothalamus of diabetics. Our discovery reveals novel hypothalamic pathophysiology, which is reminiscent of diabetic retinopathy and suggests a potential functional involvement of the hypothalamic vasculature in the later stage pathogenesis of metabolic syndrome. [Hide abstract]